Value Of New Drugs Research Articles

Validity and Reliability of Value Assessment Frameworks for New Cancer Drugs.

Several organizations have developed frameworks to systematically assess the value of new drugs. These organizations include the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the Institute for Clinical and Economic Review (ICER), and the National Comprehensive Cancer Network (NCCN). To understand the extent to which these four tools can facilitate value-based treatment decisions in oncology. In this pilot study, eight panelists conducted value assessments of five advanced lung cancer drugs using the ASCO, ESMO, and ICER frameworks. The panelists received instructions and published clinical data required to complete the assessments. Published NCCN framework scores were abstracted. The Kendall's W coefficient was used to measure convergent validity among the four frameworks. Intraclass correlation coefficients were used to measure inter-rater reliability among the ASCO, ESMO, and ICER frameworks. Sensitivity analyses were conducted. Drugs were ranked similarly by the four frameworks, with Kendall's W of 0.703 (P = 0.006) across all the four frameworks. Pairwise, Kendall's W was the highest for ESMO-ICER (W = 0.974; P = 0.007) and ASCO-NCCN (W = 0.944; P = 0.022) and the lowest for ICER-NCCN (W = 0.647; P = 0.315) and ESMO-NCCN (W = 0.611; P = 0.360). Intraclass correlation coefficients (confidence interval [CI]) for the ASCO, ESMO, and ICER frameworks were 0.786 (95% CI 0.517-0.970), 0.804 (95% CI 0.545-0.973), and 0.281 (95% CI 0.055-0.799), respectively. When scores were rescaled to 0 to 100, the ICER framework provided the narrowest band of scores. The ASCO, ESMO, ICER, and NCCN frameworks demonstrated convergent validity, despite differences in conceptual approaches used. The ASCO inter-rater reliability was high, although potentially at the cost of user burden. The ICER inter-rater reliability was poor, possibly because of its failure to distinguish differential value among the sample of drugs tested. Refinements of all frameworks should continue on the basis of further testing and stakeholder feedback.

PHP276 - Understanding Health Technology Assessment (HTA) Bodies in Major European Markets: Systematic Evaluation in 10 EU Countries

Value of new drugs are evaluated through HTAs in at least 48 countries. Their influence on evidence-based healthcare decision-making includes determining level of coverage in Europe. The characteristics, attributes and methodologies employed by HTA bodies vary significantly. Navigation through the HTA application process in multiple countries is a challenging endeavor. The objective was to characterize the different HTA methodologies used in major European markets. We conducted a systematic review of HTA bodies’ documentation of 10 markets in Europe (England & Wales, France, Germany, Italy, Netherlands, Poland, Scotland, Spain, Sweden and Switzerland) and on peer-reviewed publications through PubMed. For Italy and Spain, a prominent regional HTA was evaluated, Lombardy and Catalonia respectively. Over 350 HTA characteristics, attributes assessed and methodologies used were assessed. Among 10 HTA systems evaluated, England & Wales (NICE), Netherlands (CVZ) and Poland (AOTM) use explicitly stated incremental cost-effectiveness ratio (ICER) thresholds of £20,000-£30,000/QALY, €40,000/QALY and €26,500/QALY respectively. Three markets use implicit ICER thresholds based on the cost-effectiveness studies of previously approved drugs/technologies. Seven HTA bodies involve the general public, 6 publish reports online, 5 review within 2-6 months, and 3 allow for some form of appeal. We describe the various characteristics, attributes, and methodologies by payer architypes across Europe and discuss the associated pros and cons. Numerous HTA bodies provide support during submission process but others lack important information in the public domain. HTA bodies vary significantly and can be categorized as ones using explicit ICER thresholds and ones using implicit ICER thresholds in addition to other factors. Understanding the nuances related to HTA evaluation processes in multiple countries regarding involvement the general public, duration of review process, and ability to appeal, methods of technology assessment, preference on active controls, or availability of submission support will help manufacturers plan accordingly.

Design and evaluation of a software for the objective and easy-to-read presentation of new drug properties to physicians.

BackgroundWhen new pharmaceutical products appear on the market, physicians need to know whether they are likely to be useful in their practices. Physicians currently obtain most of their information about the market release and properties of new drugs from pharmaceutical industry representatives. However, the official information contained in the summary of product characteristics (SPCs) and evaluation reports from health agencies, provide a more complete view of the potential value of new drugs, although they can be long and difficult to read. The main objective of this work was to design a prototype computer program to facilitate the objective appraisal of the potential value of a new pharmaceutical product by physicians. This prototype is based on the modeling of pharmaceutical innovations described in a previous paper.MethodsThe interface was designed to allow physicians to develop a rapid understanding of the value of a new drug for their practices. We selected five new pharmaceutical products, to illustrate the function of this prototype. We considered only the texts supplied by national or international drug agencies at the time of market release. The perceived usability of the prototype was evaluated qualitatively, except for the System Usability Scale (SUS) score evaluation, by 10 physicians differing in age and medical background.ResultsThe display is based on the various axes of the conceptual model of pharmaceutical innovations. The user can select three levels of detail when consulting this information (highly synthetic, synthetic and detailed). Tables provide a comparison of the properties of the new pharmaceutical product with those of existing drugs, if available for the same indication, in terms of efficacy, safety and ease of use.The interface was highly appreciated by evaluators, who found it easy to understand and suggested no other additions of important, internationally valid information. The mean System Usability Scale score for the 10 physicians was 82, corresponding to a “good” user interface.ConclusionsThis work led us to propose the selection, grouping, and mode of presentation for various types of knowledge on pharmaceutical innovations in a way that was appreciated by evaluators. It provides physicians with readily accessible objective information about new drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12911-015-0158-2) contains supplementary material, which is available to authorized users.

Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report

AbstractThe current document is a revision of the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for treatment response in myelofibrosis (MF) and represents a collaborative effort by the IWG-MRT and the European LeukemiaNet to objectively assess the value of new drugs in inducing morphologic remission or improvement in MF-associated symptomatic burden (MF-SB). Some of the changes in the current revision include stricter definitions of red cell transfusion dependency and independency and consideration of the Myeloproliferative Neoplasm Symptom Assessment Form as a tool to quantify meaningful changes in disease-related symptoms. Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-SB were annotated as clinical improvement, anemia response, spleen response, or symptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The document also includes recommendations for assessing cytogenetic and molecular remissions, without mandating their inclusion for CR assignment.

Higher US Branded Drug Prices And Spending Compared To Other Countries May Stem Partly From Quick Uptake Of New Drugs

The United States spends considerably more per capita on prescription drugs than other countries in the Organization for Economic Cooperation and Development (OECD). Drawing on the Intercontinental Medical Statistics Midas database, we examined the variation in drug prices among selected OECD countries in 2005, 2007, and 2010 to determine which country paid the highest prices for brand-name drugs, what factors led to variation in per capita drug spending, and what factors contributed to the rate of increase in drug spending. We found that depending on how prices were weighted for volume across the countries, brand-name prescription drug prices were 5-198percent higher in the United States than in the other countries in all three study years. (A limitation is that many negotiated price discounts obtained in the United States may not be fully reflected in the results of this study.) A contributor to higher US per capita drug spending is faster uptake of new and more expensive prescription drugs in the United States relative to other countries. In contrast, the other OECD countries employed mechanisms such as health technology assessment and restrictions on patients' eligibility for new prescription drugs, and they required strict evidence of the value of new drugs. Similarly, US health care decision makers could consider requiring pharmaceutical manufacturers to provide more evidence about the value of new drugs in relation to the cost and negotiating prices accordingly.

New drugs—how much are they worth? The Italian registries: a model to evaluate appropriateness and effectiveness

At the 2012 EAHP congress in Milan a seminar was devoted to the value of new drugs in oncology. This article is a reflection of a presentation given during that...

Market access agreements for pharmaceuticals in Europe: diversity of approaches and underlying concepts

BackgroundMarket Access Agreements (MAA) between pharmaceutical industry and health care payers have been proliferating in Europe in the last years. MAA can be simple discounts from the list price or very sophisticated schemes with inarguably high administrative burden.DiscussionWe distinguished and defined from the health care payer perspective three kinds of MAA: Commercial Agreements (CA), Payment for Performance Agreements (P4P) and Coverage with Evidence Development (CED). Apart from CA, the agreements assumed collection and analysis of real-life health outcomes data, either from a cohort of patients (CED) or on per patient basis (P4P). We argue that while P4P aim at reducing drug cost to payers without a systematic approach to addressing uncertainty about drugs' value, CED were implemented provisionally to reduce payer's uncertainty about value of a medicine within a defined time period.SummaryWe are of opinion that while CA and P4P have a potential to reduce payers' expenditure on costly drugs while maintaining a high list price, CED address initial uncertainty related to assessing the real-life value of new drugs and enable a final HTA recommendation or reimbursement and pricing decisions. Further, we suggest that real cost to health care payers of drugs in CA and P4P should be made publicly available in a systematic manner, to avoid a perverse impact of these MAA types on the international reference pricing system.

Pharmaceuticals and the Right to Health: Reclaiming Patients and the Evidence Base of New Drugs

There has been considerable growth in clinical trials being offshored and conducted worldwide. Research on new drugs and drug development spending has skyrocketed over the past three decades, but the public benefits stemming from this boom remain limited. Because clinical trials are expensive, they often undermine the affordability and accessibility of new medicines. Once trial data has been sent off to headquarters, new problems emerge locally such as maintaining continuity of treatment for patients and ongoing attempts by trial sponsors to control patient data. This essay explores how coalitions of physicians and health policy makers in Brazil are scrutinizing the value of new drugs while securing patients' rights to high-cost medicines—and the complex political and market factors that impede such efforts. The "trial" is not only a hypothesis-testing instrument, it reinvents the doctor-patient relationship and opens new institutional and socio-medical possibilities. This analysis also serves as an ethnographic resource for physicians and patients in other low-income countries, where rights to health are constitutionally mandated but where needed medicines and their sustainable provisioning are constantly under threat.

Myeloproliferative Neoplasms: Molecular Pathophysiology, Essential Clinical Understanding, and Treatment Strategies

To update oncologists on pathogenesis, contemporary diagnosis, risk stratification, and treatment strategies in BCR-ABL1-negative myeloproliferative neoplasms, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Recent literature was reviewed and interpreted in the context of the authors' own experience and expertise. Pathogenetic mechanisms in PV, ET, and PMF include stem cell-derived clonal myeloproliferation and secondary stromal changes in the bone marrow and spleen. Most patients carry an activating JAK2 or MPL mutation and a smaller subset also harbors LNK, CBL, TET2, ASXL1, IDH, IKZF1, or EZH2 mutations; the precise pathogenetic contribution of these mutations is under investigation. JAK2 mutation analysis is now a formal component of diagnostic criteria for PV, ET, and PMF, but its prognostic utility is limited. Life expectancy in the majority of patients with PV or ET is near-normal and disease complications are effectively (and safely) managed by treatment with low-dose aspirin, phlebotomy, or hydroxyurea. In PMF, survival and quality of life are significantly worse and current therapy is inadequate. In ET and PV, controlled studies are needed to show added value and justify the risk of unknown long-term health effects associated with nonconventional therapeutic approaches (eg, interferon-alfa). The unmet need for treatment in PMF dictates a different approach for assessing the therapeutic value of new drugs (eg, JAK inhibitors, pomalidomide) or allogeneic stem-cell transplantation.

Should Financial Incentives be Used to Differentially Reward ‘Me-Too’ and Innovative Drugs?

Strategies to change the existing mix of innovative and 'me-too' drugs are intended to increase societal value of a given investment in R&D by providing an incentive for firms to invest in drugs that are more likely to be clinically innovative. How can financial incentives be used to change this mix? Will a strategy have its intended consequence or will it have the unintended outcome of reducing the rate at which the population burden of disease is reduced? The perspective of this review is a country such as Australia, Canada or the UK that has universal health insurance and a drug reimbursement process that is informed by economic evidence. A review of the literature was performed and the views of both the proponents and the opponents of such strategies and the mechanisms by which they could be implemented were summarized. The debate is based largely on hypothesized responses by firms to changes in incentives rather than empirical evidence. The main point of contention is whether a changed mix of new molecular entities (NMEs) increases or decreases the total amount of clinical innovation launched each year. The argument presented in this article is that, despite the limited empirical evidence, it is possible to improve our assessment of the likely costs and consequences of a proposed strategy by appealing to economic theory and observations about the reimbursement process. First, the empirical evidence supporting the view that changing a mix of drugs will improve clinical innovation is based on the average launched drug, not the marginal innovative drug otherwise not developed, and therefore could be misleading. Second, the dynamic and complex nature of evidence of clinical innovation will reduce the feasibility of using contractually based mechanisms to implement such a strategy. Also, a single country is unlikely to have an impact on R&D decisions, and variation in the per capita economic value of new drugs would make multi-jurisdiction contracts with one firm difficult to implement. Third, the quality of evidence of the clinical innovation of the lead drug could be reduced if there are fewer or no follow-on drugs. Finally, the existing inefficiencies in the process of displacement to finance new technologies from a capped budget reduces the efficiency with which any additional potential clinical innovation from NMEs will be translated to reduced population burden of disease. The article concludes that it is possible that such a strategy could be costly to implement, and the impact on global burden of disease uncertain in both direction and magnitude. This is likely to be the case even if the average clinical innovation content of innovative NMEs is higher than for me-too NMEs and the mechanisms designed to change the mix of NMEs are effective. Other options to improve the effectiveness with which pharmaceutical clinical innovation reduces burden of disease should be explored, including improved efficiency of both firm R&D and the process of disinvestment to finance new technologies.

Letters

To the Editor. A commentary published in July 8, 2009 Journal of the American Medical Association (JAMA) underscored the importance of Food and Drug Administration (FDA) approval documents in conducting truly independent evaluations of the therapeutic value of new drugs.1 The author concluded “…agency reviews are the most complete and accurate syntheses of clinical trial data available—it is time to make better use of them.” FDA approval packages contain rigorously reviewed data submitted by manufacturers in support of new drug approvals. These documents have been available free of charge on the agency's Web site for over a decade. Fundamental to the importance of these FDA documents is the evidence that only an estimated 30% to 50% of the randomized clinical trials submitted to the agency are published, and the majority of those that are not published appear to be trials with negative results.2,3 This, of course, may result in an overly optimistic impression of the therapeutic value of new drugs by clinicians. In addition, this raises questions about the validity of the drug information sources we as pharmacy educators traditionally have recommended to our students. These sources would include the published medical literature comprised of systematic reviews; meta-analyses; clinical practice guidelines; and the compendia and databases that depend on the peer-reviewed literature for documentation. Another important source of rigorously-reviewed, potentially-unpublished clinical trials is FDA briefing documents prepared for agency advisory committee meetings. These documents are reviews of early safety and efficacy data before a drug is approved. They are required to be in the public domain before advisory committee meetings and have been available on the FDA's Web site since 2000. The value of briefing documents may be best illustrated by the first dual peroxisome proliferator–activated receptor (PPAR) agonist muraglitazar (Pargluva) that was highly touted as a breakthrough by the professional and lay media. Nissen and colleagues using the FDA briefing documents for the muraglitazar advisory committee meeting found that the drug was found to be associated with excess of major adverse cardiovascular events.4 Approval and briefing documents can be difficult to locate due to the nature and size of the FDA Web site.5 The effective utilization of both types of documents requires more than a casual familiarity with drug regulations and a strong background in evaluating clinical research, including observational research. The importance and utilization of FDA approval and briefing documents have been a part of our 2-course drug information sequence required in the first year of our doctor of pharmacy (PharmD) curriculum for the past 4 years. This year, 2009, we have instituted a Capstone Course for our second-professionalyear students in which they are asked to evaluate the therapeutic value of a drug. Students are required to use approval documents and/or briefing documents in their evaluations. With potentially as much as half of the available data about new drugs being unpublished, we no longer find it tenable to routinely, and uncritically, teach and recommend the use of traditional drug information sources for our students. Larry D. Sasich, PharmD, MPH Sana R. Sukkari, BScPharm, MPhil, PharmD G. Elliott Cook, PharmD Donald A. Tuttle, PharmD LECOM School of Pharmacy

Do New Drugs Increase Life Expectancy? A Critique of a Manhattan Institute Paper

A recent study published by the Manhattan Institute “Why Has Longevity Increased More in Some States than in Others? The Role of Medical Innovation and Other Factors,” purported to show that the more rapid adoption of new drugs has substantial benefits in the form of increased life expectancy, higher productivity and lower non-drug health care expenditures. This study has been cited as evidence supporting the more rapid acceptance of new drugs in Medicaid, Medicare, and other public programs and has helped to shape public debate on the value of new drugs. This analysis questions the key conclusions of the study. It points out that the key statistical regressions appear to be misspecified, since they show anomalies such as a negative correlation between income growth and life expectancy and find no relationship between education and productivity growth. Methodological flaws addressed include lack of adjustment for infant mortality rates; inadequate proxy measures of health status; lack of adjustment for ages of individuals and other sociodemographic factors; inherent problems with the definition of drug age, or ‘vintage;’ and the failure to consider reverse causation as an obvious explanation for several findings. The Manhattan Institute study does not provide reliable evidence for favoring adoption of newer drugs in either public or private health care programs.

Why licensing authorities need to consider the net value of new drugs in assigning review priorities: Addressing the tension between licensing and reimbursement

Pharmaceutical regulators and healthcare reimbursement authorities operate in different intellectual paradigms and adopt very different decision rules. As a result, drugs that have been licensed are often not available to all patients who could benefit because reimbursement authorities judge that the cost of therapies is greater than the health produced. This finding creates uncertainty for pharmaceutical companies planning their research and development investment, as licensing is no longer a guarantee of market access. In this study, we propose that it would be consistent with the objectives of pharmaceutical regulators to use the Net Benefit Framework of reimbursement authorities to identify those therapies that should be subject to priority review, that it is feasible to do so and that this would have several positive effects for patients, industry, and healthcare systems.

The future of obesity: new drugs versus lifestyle interventions

Background: Obesity causes serious medical complications and impairs quality of life. However, its management remains challenging. Objective: To assist health professionals who counsel patients who are overweight or obese by discussing the possible add-on value of new drugs over lifestyle interventions. Methods: A critical analysis is made of the available evidence of the long-term efficacy of diet and exercise and/or anti-obesity agents such as orlistat, sibutramine and rimonabant. Results/conclusion: Lifestyle interventions remain the cornerstone of the treatment of obesity, but adherence is poor and long-term success is modest. Pharmacological agents may be useful adjuncts for improving weight loss and maintenance, and health outcomes, and should be continued in good responders. Drug therapy and lifestyle intervention are not opponent strategies, but should probably be combined to tackle obesity.

Haematological anticancer drugs in Europe: any added value at the time of approval?

Current European regulations only require drugs to be safe and effective, although there is heavy demand for comparative efficacy data to demonstrate the added value of new drugs. The objective of the analysis reported here was to assess the added value of new anticancer drugs for haematological malignancies that have been approved by the European Medicines Agency (EMEA) based on the clinical data provided at the time of submission. Information on the evidence supporting the approval was extracted from the European Public Assessment Reports (EPARs). Documents were surveyed for new applications and for subsequent extensions between January 1995, when the EMEA was set up, and May 2006. The added value of newly approved drugs was assessed by an algorithm that evaluates the strength of evidence based on methodological appropriateness (randomised comparison) and the importance of clinical advantage (in terms of the magnitude of benefit, hardness of outcome measures, adequacy of comparator). Eleven anticancer drugs were analysed. Of 17 indications, nine (53%) were approved on the basis of single-arm trials (SATs), and eight (47%) were approved on the basis of randomised controlled (clinical) trials (RCTs). The most frequently used endpoint was response rate (12 of 17 indications, 70%). On the basis of our criteria, only four of the 11 drugs show a consistent added value. We were unable to establish an added value for about two thirds of the drugs evaluated in this study, primarily due to methodological aspects related to study design and endpoint robustness.

Quantification et valorisation du progrès thérapeutique médicamenteux par la Haute Autorité de santé

The French National Health Authority has delegated to the Transparency Commission (TC) responsibility for defining and quantifying therapeutic progress and for certifying the therapeutic added value of new drugs. It is essential to distinguish between pharmacologic innovation and therapeutic progress. The TC considers that a new product offers therapeutic progress if it: 1) improves patient management, 2) represents a significant clinical breakthrough, and/or 3) meets a previously uncovered need. Therapeutic progress must be supported by quantitative or qualitative clinical evidence of improved therapeutic tolerance, compliance or maintenance. The TC measures progress in terms of the enhancement of therapeutic value (ETV) relative to existing products. Ideally, ETV should be evaluated in head-to-head comparisons, but companies often prefer placebo-controlled studies, meaning that indirect comparisons are unavoidable. ETV is graded in five levels, ranging from I (major progress) to V (no progress), and is attributed for a specific target population. The ETV only measures expected therapeutic progress, to be confirmed in post-registration studies. TC decisions are taken into account by the commission that determines drug prices. One pending economic issue involves "me-too" products. Indeed, scientific committees cannot be expected to regulate market competition--for example, to decide when to inform decision-makers that the number of statins or betablockers on the market is sufficient to cover requirements. Another delicate problem concerns efforts by brand-name drug companies to circumvent generic drugs, notably by introducing fixed-dose combinations. Although the assessment of therapeutic progress is based on objective, verifiable and reproducible criteria, it can only be carried out fairly within a collaborative framework independent of pharmaceutical companies, healthcare insurers and consumer associations.

Satisfaction surveys: do we really need new questionnaires?

Before introducing a new intervention in the health care setting, whether it is a technology, a new drug, or an evaluative tool, its validity must be fully tested as the final goal is to improve patients (quality of) care, as any change in patients care is potentially associated with benefits, risks, and costs. ‘Validity’ is not a yes/no attribute, but the results of the accumulation of evidence were produced through a long process where hypotheses are formulated and then sequentially challenged with several empirical testings. A good example is the process of development and validation of new drugs. The regulatory agencies that are responsible for the first evaluation of the scientific and clinical value of new drugs, generally require information on the intrinsic quality and clinical safety and efficacy of drugs before approving their introduction in the market. After an exhaustive pre-clinical evaluation, phase I and II studies on small samples of patients give information about the toxicity and activity of the new compounds. Later phase III and IV studies provide data on safety and efficacy, either in an ideal and real setting. The cornerstone of this evaluation is a formal comparison of the new drug with an appropriate control. This approach derives from the experience that some drugs have been shown to have good intrinsic pharmacological properties in early phase studies but when they were tested in more carefully controlled research …

When an Asthma Drug Has an Inferiority Complex: A Noninferiority Trial

After a new drug ascends to the regulatory summit of approval, the immediate and appropriate response by clinicians is to wonder if it has risen to a greater height of efficacy than drugs already available. The answer can depend on the outcome of clinical interest and the relative balance of clinical efficacy, safety, patient acceptability, and cost. It is against this background of uncertainty that comparison studies, typically funded by pharmaceutical companies, triangulate the relative value of new drugs compared with old. In this issue of Pediatrics , Garcia and colleagues1 report a multicenter, double-blinded, active-control, randomized trial to compare the efficacy of oral montelukast and inhaled fluticasone in children 6 to 14 years old with mild persistent asthma. The study's primary hypothesis was that montelukast was not inferior to fluticasone in the change in percent of asthma “rescue-free days” over the course of 1 year. Thus, this study is a noninferiority trial, a relatively recent study design that tests the equivalency of 1 drug to another. In the drug-approval process, an active control trial is used in place of a placebo-controlled study, when, for example, it would be unethical to randomize to a placebo. More recently, noninferiority designs have been used in postmarketing studies to establish a drug's equivalence to existing drugs in the clinical marketplace.2 The stakes in these studies are high for patients whose therapy may be modified as a result of the findings and for pharmaceutical companies selling the drugs. How should a reader evaluate … Address correspondence to David C. Goodman, MD, MS, Department of Pediatrics and the Center for the Evaluative Clinical Sciences, Dartmouth Medical School, 7251 Strasenburgh Hall, Hanover, NH 03755. E-mail: david.goodman{at}dartmouth.edu

Mechanisms of inhibitory and regulatory effects of methylenedioxyphenyl compounds on cytochrome P450-dependent drug oxidation.

Cytochrome P450 (CYP) enzymes catalyse the oxidative conversion of drugs and other lipophilic compounds to hydrophilic metabolites. Thus, CYPs play a dominant role in the elimination of drugs from the body. Inhibitory interactions occur when drugs compete for oxidation by specific CYPs whereas certain drugs increase the capacity for oxidative biotransformation by inducing the synthesis of new CYPs. Methylenedioxyphenyl (MDP) compounds have been widely employed as commercially important pesticide synergists and a number of derivatives are found in oils and spices. MDP compounds are of considerable toxicological significance because of their capacity to inhibit and induce CYP enzymes in mammals; some derivatives produce neurotoxic and hepatotoxic effects. Although there are relatively few therapeutic agents of present clinical importance that possess the MDP structural feature, the synthesis and preclinical evaluation of such agents appears to be increasing. In the context of the existing literature surrounding MDP compounds it is noteworthy that these potential drugs also elicit significant modulatory effects on CYP activities in rat and human liver. These developments indicate the importance of understanding the chemical mechanisms by which MDPs interact with CYPs. Thus, the presence of the MDP structure may undermine the potential clinical value of new drugs.

Drug safety in relation to efficacy: the view of a clinical pharmacologist.

The number of registered drugs, and drug expenditure are increasing rapidly in Europe, and within the European Union (EU) there are no longer any regulations requiring that new drugs have to be better than old ones. At the same time, pharmacoepidemiological studies in Europe and USA show that adverse drug reactions now may account for up to 10% of the admissions of patients to internal medicine wards at a cost of hundreds of millions of US dollars annually. This represents a considerable increase compared to 20 years ago. A partial explanation is the many shortcomings of many clinical trials and their relevance for health care. Adverse drug reactions are often poorly studied and documented in these studies and very seldom included in health economical analyses of the value of new drugs. Pharmacovigilance is product- rather than utilization-oriented and quite invisible in clinical medicine. This is regrettable, since up to 50% of adverse drug reactions (ADRs) are dose-dependent and thus preventable. Hopefully, the rapid progress in molecular and clinical pharmacogenetics will provide new tools for clinicians to choose and dose drugs according to the individual needs of patients.